The present invention relates generally to the use of antibodies for treatment and diagnosis of neurological diseases. More particularly, the present invention deals with the modification of antibodies so that they can be delivered through the blood-brain barrier by transcytosis.
Antibodies in general, and especially monoclonal antibodies, are widely used in diagnostic tests as a means for detecting the presence of specific antigens. Enzyme linked immunoassay and radioimmunoassay are common diagnostic techniques which utilize antibodies and detect antigens in vivo. Antigens may also be detected in vitro by administering radiolabelled antibodies to a living subject followed by external detection of radiolabelled antibody sequestered by a particular organ bearing the respective antigen. Antibodies have also been used widely in the treatment of viral infections and other diseases. However, the use of antibodies in either the treatment or diagnosis of neurological diseases has been very limited because most antibodies are not capable of traversing the blood-brain barrier (BBB) and entering the brain.
The vertebrate brain has a unique capillary system which is unlike that in any other organ in the body. The unique capillary system has morphologic characteristics which make up the blood-brain barrier. The blood-brain barrier acts as a system wide cellular membrane which separates the brain interstitial space from the blood. The unique morphologic characteristics of the brain capillaries which make up the blood-brain barrier are: (a) epithelial-like high resistance tight junctions which literally cement all endothelia of brain capillaries together, and (b) scanty pinocytosis or transendothelial channels, which are abundant in endothelia of peripheral organs. Due to the unique characteristics of the blood-brain barrier, antibodies that readily gain access to other tissues in the body are barred from entry into the brain or their rates of entry are very low.
Few strategies have been developed for introducing these antibodies into the brain which otherwise would not cross the blood-brain barrier. The most commonly used strategy involves an invasive procedure where the antibody is delivered directly into the brain. The most common procedure is the implantation of a catheter into the ventricular system to bypass the blood-brain barrier and deliver the antibody directly to the brain. Such a procedure has been used in treating echovirus encephalitis (Erlendsson et al., Successful Reversal of Echovirus Encephalitis in X-linked Hypogammablobulinemia by Intraventricular Administration of Immunoglobulin. 1985. New England Journal of Medicine. Vol. 312, No. 6. pages 351-353).
Although invasive procedures, such as the one described above, for the direct delivery of antibodies to the brain ventricles have experienced some success, they are not entirely satisfactory because they do not deliver the antibodies to the structures deep within the brain. Further, the invasive procedures are potentially harmful to the patient. Accordingly, there presently is a need to provide an improved method for delivering antibodies across the blood-brain barrier and into the brain for both diagnostic and therapeutic purposes.